NMDA receptors are unique from other glutamate receptors in that they are permeable to calcium. This calcium permeability is necessary for neuronal long-term potentiation, the cellular basis of learning and memory, and can also cause excitotoxicity and cell death in disease conditions like stroke and epilepsy. Therefore understanding mechanisms that influence gating and permeability of NMDA receptors will provide more insight to the processes that control plasticity and excitotoxicity. The gating and permeability of NMDA receptors is influenced by a variety of extracellular and intracellular signals, including protein kinase A (PKA), which is the focus of this proposal. PKA has been shown to increase both the amplitude and calcium component of NMDA currents, which then influences many types of neuronal signaling, including long-term potentiation. The mechanism by which PKA modulates NMDA receptors, however, is completely unknown. In this proposal, therefore, modulation of NMDA receptors will be investigated using two aims. The goal of the first aim is to determine the mechanism by which NMDA receptor gating and permeability are modulated by PKA using single NMDA receptor recordings, pharmacological manipulations, kinetic modeling, and site- directed mutagenesis. In the second aim, factors that regulate the modulation of NMDA receptors by PKA will be investigated, including phosphatases and neuromodulators. The results of these experiments will therefore determine the mechanism by which PKA alters NMDA receptor gating and will give insight as to how this modulation interacts with other cellular signals and may ultimately change neuronal output.